ABSTRACT - Overall The overall goal of the Measuring, Modeling and Controlling Heterogeneity Center in the Cancer Systems Biol- ogy Consortium (M2CH-CSBC Center) is to improve management of triple negative breast cancer (TNBC) by developing systems level strategies to prevent the emergence of cancer subpopulations that are resistant to treatment. We postulate that heterogeneity arising from epigenomic instability intrinsic to cancer cells and di- verse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance. We will learn how intrinsic and extrinsic factors influence differentiation state, proliferation and therapeutic re- sponse in TNBC through experimental manipulation and computational modeling of cancer cell lines, 3D engi- neered multicellular systems, xenografts and clinical specimens. We will deploy single cell `omic and imaging technologies that allow quantitative assessment of molecular, cellular, and structural heterogeneity. We will interpret these data using computational models that define control networks and structures in heterogeneous systems as well as transitions between states of therapeutic resistance and sensitivity. This will be accom- plished in three related Projects and three Cores. Project 1 will focus on measuring and managing resistance- associated heterogeneity intrinsic to cancer cells. Project 2 will focus on identifying resistance-associated sig- nals from the microenvironment and on mitigating effects from these signals on therapeutic response. Project 3 will apply spatial systems biology approaches to TNBC specimens and multicell type models thereof to dis- cover molecular control networks that influence how cell intrinsic plasticity and microenvironment signaling al- ter therapeutic responses in complex tissues. All three Projects will include analysis of 5 core cell lines (HCC1143, HCC1599, MDA-MB-468, SUM149PT, and HCC1806), 5 patient derived cultures, and 6 FDA ap- proved, pathway-targeted drugs (afatinib, ruxolotinib, trametinib, BYL719, cabozantinib, and everolimus). The computational network discovery, data integration, spatial systems analysis and modeling approaches are the same in all Projects and serve to integrate the work of the overall M2CH-CSBC Center. Multiple integrative computational strategies are proposed to identify candidate heterogeneity control networks. These include analysis of existing genomic, epigenomic, pharmacologic response, and metabolomic characteristics of prima- ry tumors and models thereof. An Imaging Management and Analysis Core will provide infrastructure and image analytics that will enable efficient image data management, quantitative analysis of image features, and visualization of images and metadata generated using multiscale light and electron microscopy. An Outreach Core will make educational materials, experimental and computational tools and data available to the CSB Consortium, to the CSBC/PS-ON Coordinating Center and to the broader scientific community. An Administrative Core serves as the organization, integration, and evaluation hub of the M2CH-CSBC Center.